This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Optimal treatment of type 1 diabetes mellitus (T1DM) should focus on physiologic insulin replacement. Insulin glargine is used as a long acting insulin (LAI) analog. Glargine is superior to NPH in decreasing nocturnal hypoglycemia and improving glycemic control. Glargine, as per manufacturer, must be given separate from rapid acting insulin (RAI), resulting in undesired multiple insulin injections. This is especially problematic in pediatric T1DM. In pediatric patients, glargine action is less than 24 hrs. We have previously demonstrated that mixing glargine with RAI, and given twice daily compared to separately given injections of RAI and glargine does not adversely affect glucose excursions. Furthermore, we demonstrated that 3 months of twice-daily glargine mixed with RAI results in a 30% improvement in HbA1C as compared to standard therapy of NPH and RAI. Detemir is a new long-acting insulin analog. In this proposal, we aim to study the efficacy of detemir in pediatric T1DM, and compare it to the gold standard of using glargine. Since there is no data regarding mixing insulin, in this protocol, detemir will be mixed with RAI in the same syringe, and be compared with giving them as separate injections twice-daily. 1. Insulin detemir mixed with RAI analog given twice daily will have equivalent effects on lowering blood glucose vs. giving insulin detemir and RAI as separate injections twice daily, in the treatment of pediatric T1DM. 2. Glucose excursions will be similar with the use of either detemir or glargine when either of the two is given mixed with RAI as a twice-daily injection. Insulin glargine was the first long-acting insulin analog to be produced by recombinant DNA technology [2,3]. Early pharmacokinetic (pK) studies with insulin glargine in healthy volunteers reported a duration of action of up to 30 h [4]. However, the duration was significantly shorter with mean plasma glucose levels in euglycemic clamp studies rising 16 h after glargine administration with the mean duration of action for the entire study population being 20.5 h [5]. There are limited pK data available in the pediatric population and clinical practice suggests that glargine lasts for a much shorter period of time in some patients with T1DM [6]. Despite the benefits of intensive insulin management, the use of long-acting analogs is associated with poor compliance [7] and adherence to treatment plans. This is due to the increased number of injections that are required to maintain euglycemia as compared to standard therapy of NPH as a basal injection. To overcome this obstacle we hypothesized that although there may be some pK variation when insulin glargine is mixed with short acting analogs it may not affect pharmacodynamic (pD) profile significantly. To prove this, we recruited subjects who were on once a day insulin glargine and used continuous glucose monitoring system (CGMS) to obtain 3 days glucose profiles. Subjects were then randomized to either receiving insulin glargine twice a day mixed with RAI analogs or insulin glargine given twice a day separate from the RAI analogs. CGMS was obtained after each of these treatment plans and no difference in glucose concentrations were detected when insulin glargine was given mixed or given separately from the RAI [8]. However, the long-term effects of mixing on glycemic control could not be evaluated because subjects were on this regimen for only 10 days. In trial 2, currently in progress, long-term glycemic effects of mixing insulin glargine with RAI and administering it as a twice-daily dose and comparing its effect to twice-a-day NPH is being examined (See preliminary data). New onset T1DM subjects were recruited and at 3 months were randomized to either receiving NPH and RAI mixed and given as a twice a day regimen vs. insulin glargine and RAI mixed and given as a twice a day regimen. At the end of 3 months, we found that subjects on twice daily glargine mixed with had a significantly better hemoglobin A1c (HbA1c) (NPH vs. glargine 7.5% Vs 6.3%) as compared to the NPH arm (p<0.03). These studies suggest that some pK variation when insulin glargine is mixed with RAI (discussions with Sanofi-Aventis) may not be of clinical significance. Furthermore, the ability to mix insulins results in fewer injections, which increases compliance in all T1DM subjects but makes an immense difference in children with T1DM.